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Loss of TDP-43 in astrocytes leads to motor deficits by triggering A1-like reactive phenotype and triglial dysfunction
15 auth. Audrey Yi Tyan Peng, Ira Agrawal, W. Y. Ho, Y. Yen, Ashley J Pinter, Jerry Liu, Qi Xuan Cheryl Phua, Katrianne Bethia Koh, Jer-Cherng Chang, E. Sanford, ...
Significance Aberrant TDP-43 aggregation is one of the defining pathological hallmark proteins of two overlapping adult-onset neurodegenerative diseases, amyotrophic lateral sclerosis and frontotemporal dementia. While TDP-43 aggregates are also fou…
Significance Aberrant TDP-43 aggregation is one of the defining pathological hallmark proteins of two overlapping adult-onset neurodegenerative diseases, amyotrophic lateral sclerosis and frontotemporal dementia. While TDP-43 aggregates are also found in astrocytes, it is not known how loss of astroglial TDP-43 affects neuronal function and disease pathogenesis. Herein, we show that TDP-43 is required for maintaining the protective properties of astrocytes, such that loss of astroglial TDP-43 causes triglial abnormalities that result in motor deficits. These findings establish that TDP-43–mediated dysfunction in different cell types uniquely contributes to neurodegenerative disease through cell-type–specific mechanisms. Delineating these etiologies could facilitate the discovery of novel strategies to treat neurological disorders caused by TDP-43 proteinopathy. Patients with amyotrophic lateral sclerosis (ALS) can have abnormal TDP-43 aggregates in the nucleus and cytosol of their surviving neurons and glia. Although accumulating evidence indicates that astroglial dysfunction contributes to motor neuron degeneration in ALS, the normal function of TDP-43 in astrocytes are largely unknown, and the role of astroglial TDP-43 loss to ALS pathobiology remains to be clarified. Herein, we show that TDP-43–deleted astrocytes exhibit a cell-autonomous increase in GFAP immunoreactivity without affecting astrocyte or microglia proliferation. At the transcriptomic level, TDP-43–deleted astrocytes resemble A1-reactive astrocytes and induce microglia to increase C1q expression. These astrocytic changes do not cause loss of motor neurons in the spinal cord or denervation at the neuromuscular junction. In contrast, there is a selective reduction of mature oligodendrocytes, but not oligodendrocyte precursor cells, suggesting triglial dysfunction mediated by TDP-43 loss in astrocytes. Moreover, mice with astroglial TDP-43 deletion develop motor, but not sensory, deficits. Taken together, our results demonstrate that TDP-43 is required to maintain the protective functions of astrocytes relevant to the development of motor deficits in mice.
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5 | 2020 |
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